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  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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  • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
  • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
  • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
  • C07C311/46—Y being a hydrogen or a carbon atom
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  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
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  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
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  • C07C2602/00—Systems containing two condensed rings
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  • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

• the present invention relates to novel tyrosine alkoxyguanidine compounds that are inhibitors of alpha V ( ⁇ v) integrins, for example ⁇ v ⁇ 3 and ⁇ v ⁇ 5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
• ⁇ v alpha V
• Integrins are cell surface glycoprotein receptors which bind extracellular matrix proteins and mediate cell-cell and cell-extracellular matrix interactions (generally referred to as cell adhesion events) (Hynes, R.O., Cell 69:11-25 ( 1992)). These receptors are composed of noncovalently associated alpha ( ) and beta ( ⁇ ) chains which combine to give a variety of heterodimeric proteins with distinct cellular and adhesive specificities (Albeda, S.M., Lab. Invest. 68:4-14 (1993)). Recent studies have implicated integrins in the regulation of cellular adhesion, migration, invasion, proliferation, apoptosis and gene expression (Albeda, S.M., Lab. Invest.
• integrin ⁇ v ⁇ 3, or vitronectin receptor (Brooks, P.C., DN&P 10(8):456-46l (1997)).
• This integrin binds a variety of extracellular matrix components and other ligands, including fibrin, fibrinogen, fibronectin, vitronectin, laminin, thrombospondin, and proteolyzed or denatured collagen (Cheresh, D.A., Cancer Met. Rev. 10:3-10 (1991) and Shattil, S.J., Thromb. Haemost. 74:149-155 (1995)).
• ⁇ v ⁇ 5 and ⁇ v ⁇ l also vitronectin receptors
• ⁇ v ⁇ 5 and ⁇ v ⁇ l are more specific and bind vitronectin ( ⁇ v ⁇ 5) or fibronectin and vitronectin ( ⁇ v ⁇ l) exclusively (Horton, M., Int. J. Exp. Pathol. 77:741-759 (1990)).
• ⁇ v ⁇ 3 and the other integrins recognize and bind to their ligands through the tripeptide sequence Arg-
• Gly-Asp (Cheresh, D.A., Cancer Met. Rev. 70:3-10 (1991) and Shattil, S.J., Thromb. Haemost. 7 :149-155 (1995)) found within all the ligands mentioned above.
• ⁇ v ⁇ 3 integrin has been implicated in a number of pathological processes and conditions, including metastasis and tumor growth, pathological angiogenesis, and restenosis.
• pathological processes and conditions including metastasis and tumor growth, pathological angiogenesis, and restenosis.
• ⁇ v ⁇ 3 has been implicated in the metastatic cascade (Cheresh, D.A., Cancer Met. Rev. 70:3-10 (1991); Nip, J. et al., J. Clin. Invest. 95:2096-2103 (1995); and Yun, Z., et al., Cancer Res. 5(5:3101-3111 (1996)).
• ⁇ v ⁇ 3 has also been implicated in angiogenesis, which is the development of new vessels from preexisting vessels, a process that plays a significant role in a variety of normal and pathological biological events. It has been demonstrated that ⁇ v ⁇ 3 is up-regulated in actively proliferating blood vessels undergoing angiogenesis during wound healing as well as in solid tumor growth. Also, antagonists of ⁇ v ⁇ 3 have been shown to significantly inhibit angiogenesis induced by cytokines and solid tumor fragments (Brooks, P.C., et al., Science 264:569-511 (1994); Enenstein, J. and Kramer, R.H., J. Invest. Dermatol. 705:381-386 (1994); Gladson, C.L., J. Neuropathol.
• ⁇ v ⁇ 3 antagonists would be useful for treating conditions that are associated with pathological angiogenesis, such as rheumatoid arthritis, diabetic retinopathy, macular degeneration, and psoriasis (Nicosia, R.F. and Madri, J.A., Amer. J. Pathol. 725:78-90 (1987); Boudreau, N. and Rabinovitch, M., Lab. Invest.
• ⁇ v ⁇ 3 plays a role in neointirnal hyperplasia after angioplasty and restenosis.
• peptide antagonists and monoclonal antibodies directed to both ⁇ v ⁇ 3 and the platelet receptor IIb ⁇ 3 have been shown to inhibit neointirnal hyperplasia in vivo (Choi, E.T., et al, J. Vase. Surg.
• ⁇ v ⁇ 3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption. When bone resorbing activity exceeds bone forming activity, the result is osteoporosis, a condition which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of ⁇ v ⁇ 3 have been shown to be potent inhibitors of osteoclastic activity both in vitro (Sato, M., et al, J. Cell Biol 777 : 1713- 1723 ( 1990)) and in vivo (Fisher, J.E., et al. , Endocrinology 752:1411-
• ⁇ v ⁇ 5 integrin has been implicated in pathological processes as well. Friedlander et al. have demonstrated that a monoclonal antibody for ⁇ v ⁇ 5 can inhibit VEGF-induced angiogenesis in rabbit cornea and chick chorioalloantoic membrane, indicating that the ⁇ v ⁇ 5 integrin plays a role in mediating growth factor-induced angiogenesis (Friedlander, M.C., et al, Science 270:1500-1502 (1995)).
• Compounds that act as ⁇ v ⁇ 5 antagonists could be used to inhibit pathological angiogenesis in tissues of the body, including ocular tissue undergoing neovascularization, inflamed tissue, solid tumors, metastases, or tissues undergoing restenosis.
• ⁇ v ⁇ 3 and ⁇ v ⁇ 5 have led to an interest in these integrins as potential therapeutic targets, as suggested in the preceding paragraphs.
• a number of specific antagonists of ⁇ v ⁇ 3 and ⁇ v ⁇ 5 that can block the activity of these integrins have been developed.
• One major group of such antagonists includes nonpeptide mimetics and organic-type compounds.
• a number of organic non-peptidic mimetics have been developed that appear to inhibit tumor cell adhesion to a number of ⁇ v ⁇ 3 ligands, including vitronectin, fibronectin, and fibrinogen (Greenspoon, N., etal , Biochemistry 52: 1001 - 1008 (1993); Ku, T.
• B is -CH 2 CONH- , -CONR 52 -(CH 2 ) p - , -C(O)O- , -SO 2 NH- , -CH 2 O- , or -OCH 2 - ;
• Y 1 is selected from the group consisting of N-R 2 , O and S;
• Y 3 and Z 3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl, or Y 3 and Z 3 taken together with C form a carbonyl;
• R 50 is selected from the group consisting of H, alkyl, aryl, carboxyl derivative and - CONHCH 2 CO 2 R 53 , wherein R 53 is H or lower alkyl;
• R 51 is selected from the group consisting of H, alkyl, carboxyl derivatives, -NC02R 54 , -NHSO R 54 . NHCONHR 54
• R 54 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, aralkenyl and aryl substituted by one or more alkyl or halo; and wherein R 55 is selected from the group consisting ofN-substituted pyrrolidinyl, piperidinyl and morpholinyl.
• the publication also discloses the use of the compounds as ⁇ v ⁇ 3 integrin antagonists.
• X is C,. 6 alkylene or 1 ,4-piperidyl
• Y is absent, O, CONH or -C ⁇ C-;
• R 2 and R 3 are independently H, A, A-SO 2 -, Ar-SO 2 -, camphor- 10-SO 2 -, COO A or a conventional amino protective group;
• a and R 4 are independently H, C,. 10 alkyl, or benzyl; and Ar is phenyl or benzyl, each of which is unsubstituted or monosubstituted by CH 3 ; and their physiologically acceptable salts.
• the disclosed compounds are described as ⁇ v-integrin inhibitors (especially ⁇ v ⁇ 3 inhibitors) useful in the treatment of tumors, osteoporoses, and osteolytic disorders and for suppressing angiogenesis.
• X can be, among other groups, alkyl, aryl or cycloalkyl
• R 2 is A, aryl or aralkyl
• R 3 is hydrogen or A
• R 4 is hydrogen, halogen, OA, NHA, NAN, - ⁇ H-Acyl, -O-Acyl, C ⁇ , ⁇ O 2 , SA, SON SO 2 A, SO 2 Ar or SO 3 H;
• a and A' can be hydrogen, alkyl or cycloalkyl.
• the publication discloses the use of the compounds in pharmaceutical preparations for the treatment of thrombosis, infarction, coronary heart disease, tumors, arteriosclerosis, infection and inflammation.
• the present invention is directed to novel tyrosine alkoxyguanidine compounds having Formula IF (below). Also provided is a process for preparing compounds of Formula IV. The novel compounds of the present invention exhibit inhibition of ⁇ v ⁇ 3 and ⁇ v ⁇ 5 integrin receptor binding. Also provided is a method of treating ⁇ v ⁇ 3 integrin- and ⁇ v ⁇ 5 integrin-mediated pathological conditions such as tumor growth, metastasis, osteoporosis, restenosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis in a mammal in need of such treatment comprising administering to said mammal an effective amount of a compound of Formula IV. Further provided is a pharmaceutical composition comprising a compound of Formula IV and one or more pharmaceutically acceptable carriers or diluents.
• the present invention is directed to compounds of Formula IV:
• R 1 and R 2 independently represent hydrogen, alkyl, aralkyl, R 12 SO 2 , R 12 OOC, or R 12 CO, where R 12 is (i) hydrogen, or (ii) alkyl, cycloalkyl, camphor- 10-yl, alkenyl, alkynyl, heterocycle,, aryl, aralkyl, or aralkenyl, any of which can be optionally substituted by one or more alkyl, alkenyl, aryl, aryloxy (further optionally substituted by nitro, halo, or cyano), aralkyl, aryldiazenyl (further optionally substituted by amino, alkylamino, or dialkylamino), alkoxy, haloalkyl, haloalkoxy, alkylcarbonylamino, alkylsulfonyl, mono- or di-alkylamino, hydroxy, carboxy, cyano, nitro, halo
• R 3 is hydrogen or a functionality which acts as a prodrug (i.e., converts to the active species by an endogenous biological process such as an esterase, lipase, or other hydrolases), such as alkyl, aryl, aralkyl, dialkylaminoalkyl,
• R 4 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di- alkylamino;
• R 5 , R 6 , and R 7 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl; or R 4 and R 5 are taken together to form -(CH 2 ) y -, where y is zero (a bond), 1 or 2, while R 6 and R 7 are defined as above; or R 4 and R 7 are taken together to form -(CH 2 ) q -, where q is zero (a bond), or 1 to 8, while R 5 and R 6 are defined as above; or R 5 and R 6 are taken together to form -(CH 2 ) r -, where r is 2-8, while R 4 and R 7 are defined as above;
• R 8 is hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
• R 9 , R 10 , and R" are independently hydrogen, alkyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or -COOR w ;
• R w is alkyl, cycloalkyl, phenyl, benzyl,
• R a and R D are independently hydrogen, alkyl, alkenyl or phenyl;
• R c is hydrogen, alkyl, alkenyl or phenyl;
• R d is hydrogen, alkyl, alkenyl or phenyl; and
• R e is aralkyl or alkyl;
• n is from zero to 8;
• m is from zero to 4; provided that n is other than zero when R 4 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di- alkylamino.
• Preferred compounds of the present invention are those of Formula IV wherein: R 1 and R 2 independently represent hydrogen, C,. 6 alkyl, C 6 ., 0 ar(C,. 6 ) alkyl,
• R 12 SO 2 , R 12 OOC or R 12 CO where R 12 is hydrogen, C, .6 alkyl, C 6 . 10 ar(C,. 6 ) alkyl, C 4 . 7 cycloalkyl(C M )alkyl, camphor- 10-yl, or C 6 . 10 aryl substituted by one or more (C,. 6 )alkyl, (C 2.6 )alkenyl, C 6.10 aryl, C 6.10 ar(C, .6 )alkyl, C 6 . 10 aryloxy (further optionally substituted by nitro, halo, or cyano), C 6 .
• aryldiazenyl (further optionally substituted by amino, C M alkylamino or di (C,. 4 ) alkylamino), C,. 6 alkoxy, halo(C,. 6 )alkyl, halo ⁇ . alkoxy, C, .6 alkylcarbonylamino, C,. 6 alkylsulfonyl, mono- or di-(C galley lamino, hydroxy, carboxy, cyano, nitro, halo, or a heteroaryl which is optionally substituted with one or more C,.
• R 12 can also be N-attached pyrrolidinyl, piperidinyl or morpholinyl.
• R 1 examples include hydrogen and methyl.
• Preferred values of R 2 include hydrogen, t-butylcarbonyl, butylsulfonyl, propylsulfonyl, benzylsulfonyl, pentylsulfonyl, 4-tolylsulfonyl, and camphor- 10- sulfonyl.
• Especially preferred compounds are those of Formula IV wherein: R 1 is hydrogen; and
• R 2 is R 12 SO 2 , where R 12 is hydrogen, C,. 6 alkyl, C 4 . 7 cycloalkyl, camphor- 10-yl, (C 2 . 6 )alkenyl, (C 2 . 6 )alkynyl, thienyl, thiazolyl, benzo[b]thiophenyl, pyrazolyl, chromanyl, imidazolyl, benzo[2,3-c]l,2,5-oxadiazole, C 6.10 aryl, C 6 . 10 ar(C, .6 )alkyl, or C 6 . 10 ar(C 2 . 6 )alkenyl, any of which can be optionally substituted by one or more C,.
• Suitable values of R 12 include methyl, butyl, chloropropyl, phenyl, benzyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, tert-butylphenyl, pentylphenyl, phenylphenyl, camphoryl, nitrophenyl, nitrophenylmethyl, cyanophenyl, chlorophenyl, fluorophenyl, bromophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, acetylaminophenyl, butoxyphenyl, biphenyl, vinylphenyl, methoxyphenyl, methylsulfonylphenyl, 4-(3-chloro-2- cyanophenoxy)phenyl, 4-( 1 , 1 -dimethylpropyl)pheny 1, 6-chloro-2-methylphenyl, 2-methyl-5-nitrophenyl, 2,3,
• Preferred R 3 groups include hydrogen, C,. 6 alkyl and benzyl.
• R examples include hydrogen, C,_ 6 alkyl, C 6 . 10 ar(C,. 6 )alkyl, C 6-10 aryl, C 2.10 hydroxyalkyl, C 2 . 10 aminoalkyl, C 2.7 carboxyalkyl, mono(C,. 4 alkyl)amino(C 1 . 8 )alkyl, and di(C alkyl)amino(C, .8 )alkyl.
• Suitable values of R 4 include methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3- hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl, 3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl.
• Preferred compounds are those of Formula IV in which R 5 , R 6 and R 7 are independently hydrogen, C,. 6 alkyl, C 6 . 10 ar(C, .6 )alkyl, C 6.10 aryl, C 2 . 10 hydroxyalkyl or C 2 . 7 carboxyalkyl.
• R 5 , R 6 , and R 7 include hydrogen, methyl, ethyl, propyl, «-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3- hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl.
• R 5 , R° and R 7 are each hydrogen.
• R 8 include hydrogen or C,_ 6 alkyl.
• Preferred values of R 9 , R 10 and R 11 in Formula IV include hydrogen, hydroxy, C,_ 6 alkyl, C,. 6 alkoxy, cyano or-CO 2 R , where R w , in each instance, is preferably one of C,. 4 alkyl, C 4 . 7 cycloalkyl, phenyl, or benzyl.
• Suitable values of R 9 , R 10 and R" include hydrogen, methyl, ethyl, propyl, «-butyl, hydroxy, methoxy, ethoxy, cyano, -CO 2 CH 3 ,-CO 2 CH 2 CH 3 and-CO 2 CH 2 CH 2 CH 3 .
• R 9 , R 10 and R" are each hydrogen.
• n in Formula IV include zero to 6, more preferably zero to 4, and most preferably zero, 1 , or 2.
• Preferred values of m include zero to 4, and most preferably zero, 1 , or 2.
• the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
• alkyl refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
• alkenyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl, and the like.
• the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
• alkoxy is used herein to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, «-propoxy, isopropoxy, and the like.
• the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
• aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
• aryloxy as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, bonded to an oxygen atom. Examples include, but are not limited to, phenoxy, naphthoxy, and the like.
• heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1 , 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl
• aralkyl or "arylalkyl” as employed herein by itself or as part of another group refers to C,. 6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
• cycloalkyl as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
• heterocycle represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
• heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl
• monoalkylamine as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
• dialkylamine as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
• hydroxyalkyl refers to any of the above alkyl groups substituted by one or more hydroxy 1 moieties.
• carboxyalkyl refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
• haloalkyl refers to any of the above alkyl groups substituted by one or more chlorine, bromine, fluorine or iodine with fluorine and chlorine being preferred, such as chloromethyl, iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2-chloroethyl.
• haloalkoxy refers to any of the above haloalkyl groups bonded to an oxygen atom, such as trifluromethoxy, trichloromethoxy, and the like.
• Another aspect of the present invention is a process for preparing a tyrosine alkoxyguanidine compound of Formula IV, comprising reacting a compound of Formula V:
• Preferred deprotection reagents include hydrazine or methylamine.
• Preferred guanidinylating reagents include aminoiminosulfonic acid, lH-pyrazole-1-carboxamidine hydrochloride, N, N'-bis(tert-butoxycarbonyl)-S-methylisothiourea, or N-R 9 , N-R 10 -lH-pyrazole-l-carboxamidine, where R 9 and R 10 are defined as above.
• the compounds of the present invention may be prepared by the general procedures outlined in Schemes /, II, and III (below), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R w , n, and m are as defined above.
• the carboxamides 3 may be produced by the reaction of 2 with carboxylic acids (R 12 COOH) by any of the known peptide coupling reagents, such as 1,3-dicyclohexylcarbodiimide or Castro's reagent (BOP) (Castro, B., et al., Tetrahedron Lett. 1219 (1975)).
• carboxylic acids R 12 COOH
• BOP Castro's reagent
• reductive amination of 2 can be achieved by reaction with an aldehyde (R 12 COH) under reducing conditions.
• the preferred reducing agent is tetramethylammonium triacetoxyborohydride.
• sodium triacetoxyborohydride or sodium cyanoborohydride may be used.
• reductive amination may be carried out by forming an imine (Schiff base) between the amine and the carbonyl component using a catalytic amount of acid such as />-toluenesulfonic acid, followed by reduction with sodium cyanoborohydride.
• the imine may be reduced using catalytic hydrogenation using a catalyst such as palladium on carbon in a standard solvent such as ethanol.
• the amine 2 may be reacted with R 12 CH 2 L, where L is a reactive leaving group, such as a halide or sulfonate.
• the phenolic functionality of 4 is coupled to 5, where L is a reactive leaving group such as halide or sulfonate, under basic conditions, such as cesium carbonate in a solvent such asNN-dimethylformamide.
• L is a reactive leaving group such as halide or sulfonate
• the alcohol functionality may be protected with P a , an orthogonally selective functionality to the ester functionality (i.e., benzyl ethers would not be used with a benzyl ester). Removal of the optional alcohol protecting group P a is routinely accomplished using the reaction conditions well known in the art. For example, deprotection of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
• Deprotection of an acetate protecting group is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous tetrahydrofuran.
• Preferred coupling conditions include using a trialkylphosphine or triarylphosphine, such as tri- «-butylphosphine or triphenylphosphine, in a suitable solvent, such as tetrahydrofuran or dichloromethane, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or 1 , 1 '-(azodicarbonyl)dipiperidine.
• Alcohol 6 is converted to 7 employing a Mitsunobu reaction with an
• N-hydroxy cyclic imide derivative such as N-hydroxyphthalimide.
• Unveiling of the phthalimide protecting group of 7 is accomplished using standard conditions well known in the art (Greene,T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, Inc. New York ( 1991 )), for example using hydrazine or methylamine.
• R 9 and R 10 are protecting groups, for example t-butyloxycarbonyl (Boc), the compound can be optionally reacted with R"OH using standard Mitsunobu reaction condition as reviewed above to produce alkylated compounds 9.
• protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or by HC1 gas dissolved in a suitable solvent, such as 1 ,4-dioxane to produce targeted compounds 10.
• These protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or by HC1 gas dissolved in a suitable solvent, such as 1,4-dioxane to produce targeted compounds 14.
• acid usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water
• HC1 gas dissolved in a suitable solvent such as 1,4-dioxane
• the aminooxy nitrogen of 10 and 14 may be optionally alkylated using basic conditions such as solid sodium bicarbonate in a suitable solvent such as NN-dimethylformamide with R 8 X, where X is a reactive leaving group such as a halide or sulfonate to give 15.
• 15 may be reacted with pyrocarbonates such as diethyl pyrocarbonate in a suitable solvent such as acetonitrile or NN-dimethylformamide in the presence of a tertiary amine base such as NN-diisopropylethylamine to give carbamates of either mono- or di- substitution on the amidino nitrogens as in 16 and 17 as well as tri-carbamates with additional substitution on the aminooxy nitrogen as in 18.
• pyrocarbonates such as diethyl pyrocarbonate in a suitable solvent such as acetonitrile or NN-dimethylformamide
• a tertiary amine base such as NN-diisopropylethylamine
• the present invention a method of treating ⁇ v ⁇ 3 integrin- or ⁇ v ⁇ 5 integrin-mediated conditions by selectively inhibiting or antagonizing ⁇ v ⁇ 3 and ⁇ v ⁇ 5 cell surface receptors, which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted by Formula IV, wherein one or more compounds of Formula IV is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
• the present invention provides a method for inhibition of the ⁇ v ⁇ 3 cell surface receptor.
• the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget's disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and other neo-vascular eye diseases, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including neointirnal hyperplasia and restenosis.
• the present invention also provides a method for inhibition of the ⁇ v ⁇ 5 cell surface receptor.
• the present invention provides a method for inhibiting angiogenesis associated with pathological conditions such as inflammatory disorders such as immune and non-immune inflammation, chronic articular rheumatism and psoriasis, disorders associated with inappropriate or inopportune invasion of vessels such as restenosis, capillary proliferation in atherosclerotic plaques and osteoporosis, and cancer associated disorders, such as solid tumors, solid tumor metastases, angiofibromas, retrolental fibroplasia, hemangiomas, Kaposi sarcoma and similar cancers which require neovascularization to support tumor growth.
• pathological conditions such as inflammatory disorders such as immune and non-immune inflammation, chronic articular rheumatism and psoriasis, disorders associated with inappropriate or inopportune invasion of vessels such as restenosis, capillary proliferation in atherosclerotic plaques and osteoporosis, and
• the present invention also provides a method for treating eye diseases characterized by angiogenesis, such as diabetic retinopathy, age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity, and neovascular glaucoma.
• angiogenesis such as diabetic retinopathy, age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity, and neovascular glaucoma.
• the compounds of the present invention are useful in treating cancer, including tumor growth, metastasis and angiogenesis.
• compounds of the present invention can be employed to treat breast cancer and prostate cancer.
• the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.01 mg/kg to about 300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body weight.
• Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• compositions of the present invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention.
• animals Foremost among such animals are humans, although the invention is not intended to be so limited.
• compositions of the present invention can be administered by any means that achieve their intended purpose.
• administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.
• administration can be by the oral route.
• the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
• the pharmaceutical preparations of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
• the pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
• pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
• Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
• fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth,
• disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
• Auxiliaries are, above all, flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
• Dragee cores are provided with suitable coatings, that, if desired, are resistant to gastric juices.
• concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
• suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used.
• Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
• Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
• the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils or liquid paraffin.
• stabilizers may be added.
• Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example water- soluble salts and alkaline solutions.
• alkaline salts are ammonium salts prepared, for example, with Tris, choline hydroxide, bis-Tris propane, N-methylglucamine, or arginine.
• suspensions of the active compounds as appropriate oily injection suspensions can be administered.
• Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
• Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol, and/or dextran.
• the suspension may also contain stabilizers.
• the compounds of the present invention may be administered to the eye in animals and humans as a drop, or within ointments, gels, liposomes, or biocompatible polymer discs, pellets or carried within contact lenses.
• the intraocular composition may also contain a physiologically compatible ophthalmic vehicle as those skilled in the art can select using conventional criteria.
• the vehicles may be selected from the known ophthalmic vehicles which include but are not limited to water, polyethers such s polyethylene glycol 400, polyvinyls such as polyvinyl alcohol, povidone, cellulose derivatives such as carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose, petroleumn derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, vegetable fats such as peanut oil, polymers of acrylic acid such as carboxylpolymethylene gel, polysaccharides such as dextrans and glycosaminoglycans such as sodium chloride and potassium, chloride, zinc chloride and buffer such as sodium bicarbonate or sodium lactate. High molecular weight molecules can also be used.
• polyethers such as polyethylene glycol 400
• polyvinyls such as polyvinyl alcohol, povidone
• cellulose derivatives such as carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose
• petroleumn derivatives such as mineral oil and white petrolatum
• Physiologically compatible preservatives which do not inactivate the compounds of the present invention in the composition include alcohols such as chlorobutanol, benzalknonium chloride and EDTA, or any other appropriate preservative known to those skilled in the art.
• the ethyl acetate was dried and evaporated to dryness.
• the residue was purified on a silica gel column (10 g Waters Sep-Pak) by eluting with a gradient of ethyl acetate and hexane from 20:80 to 30:70. The pure fractions were combined and evaporated to dryness to give the title compound (0.269 g, 63% yield) as a clear oil.
• the mixture was stirred at room temperature for 5 h and monitored by TLC. After the reaction was complete, the mixture was filtered on a pad of Celite. The solvent of the filtrate was removed under reduced pressure.
• the assay is based on the method of Dennis (Dennis, M. S., et al, Proteins 15: 312-321 (1993)). Costar 9018 flat-bottom 96-well ELISA plates were coated overnight at 4°C with 100 ⁇ L/well of 10 ⁇ g/mL human fibrinogen
• the assay was based on the method of Niiya (Niiya, K., et al, Blood 70:475-483 (1987)).
• Costar 9018 flat-bottom 96-well ELISA plates were coated overnight at 4°C with 100 ⁇ L/well of 0.4 ⁇ g/mL human ⁇ v ⁇ 3 (Chemicon CC10118) in TS buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM CaCl 2 ,
• the plate was then washed 5 times with TS buffer, and 100 ⁇ L/well of 1 ⁇ g/mL NeutrAvidin- horseradish peroxidase conjugate (Pierce 31001 ) in TSB buffer was incubated for 1 hr. Following a 5 -fold TS buffer wash, the plate was developed and results were calculated as described for the fibrinogen-IIbllla assay.
• a representative plot for inhibition of the ⁇ v ⁇ 3-vitronectin interaction by the compound of Example 1 is shown in Figure 2.
• IC 50 values for inhibition of the ⁇ v ⁇ 3- vitronectin interaction by other compounds of the invention are presented in Table I.
• Compounds of the present invention also have v ⁇ 5 activity as determined by the SKBR3 cell-vitronectin ( ⁇ v ⁇ 5-mediated) adhesion assay described by Luna et al. (Lab. Invest. 75(4):563-513 (1996)).
• FIG. 1 E ⁇ x. 1 (nM)
• All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
• the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
• the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
• An intravenous dosage form of the compound of Example 1 ("active compound") is prepared as follows:
• the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland (1994).

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